Abstract: Optical Coherence Tomography (OCT) has greatly advanced the diagnosis and management of many retinal diseases by enabling volumetric structural imaging of the retina. Usually, retinal OCT is performed at near- infrared (NIR) wavelengths, limiting both axial resolution and contrast for molecules that play a role in vision. Though NIR OCT defines biomarkers that quantify progression of dry age-related macular degeneration (AMD), NIR OCT cannot yet delineate the finest structural and functional changes that define incipient AMD, or predict geographic atrophy, an end stage of AMD. Visible light OCT holds the promise of unprecedented axial resolution and molecular contrast, but visible light OCT systems to date have not delivered on this promise. Recently, our group identified numerous technical barriers, some unknown to the community, in visible light OCT. With our innovative solutions, we can now directly image and individually quantify Bruch?s membrane, the retinal pigment epithelium (RPE), and fine photoreceptor layers in morphologically normal retina without clinically detectable pathology, at a level of detail not attained by NIR OCT systems. These imaging capabilities are further enhanced by quantitative molecular information provided by visible light. In this proposal, we will develop fiber-based visible light OCT instrumentation and protocols to assess sub-micron changes with aging and macular degeneration in human eyes. Employing a range of in vitro and in vivo studies in rodents and humans, we propose to validate protocols that topographically measure the outer retina, RPE, and BM morphology, photopigment and melanin density, and photoreceptor function. We will validate and test the reproducibility of these structural and functional measurements, and apply them to study age-related changes in a cross-section of normal subjects. Finally, we will perform pilot clinical imaging studies to firstly, compare aging to early AMD, and secondly, identify candidate early biomarkers for progression of drusen to atrophy. If successful, this proposal will lay the groundwork for more extended longitudinal studies to study AMD progression in the human retina, and incorporation of new biomarkers into clinical trials.